1. Field of the Invention
The present invention relates to compositions of cyanoacrylate monomer, a method of improving the viscosity and the curing speed with a single additive and a process of providing sterilized cyanoacrylate adhesive compositions for application in the medical field.
2. Description of Related Art
Adhesive compositions based upon cyanoacrylate ester are known and have been used extensively in different fields due to their excellent long-term bond strength and applicability to a large range of substrates. These adhesive compositions are used as industrial and structural adhesives, consumer product for repair of household items and in the hobby sector for assembly and repair. In addition, cyanoacrylate compositions have found application in medicine for closing wounds especially in cases where suturing does not provide satisfactory results. Cyanoacrylate esters are used in protecting surface injuries including abrasions, lacerations, sores, burns and other open surface wounds.
In spite of their interesting properties and wide applications in different fields, certain factors have been an impediment to further application of cyanoacrylate adhesive compositions. One of the problems encountered results from the low inherent viscosity of cyanoacrylate monomers. Another related issue is the slow cure speed provided by certain cyanoacrylate compositions after stabilization of the compositions with various polymerization inhibitors. In addition, some cyanoacrylate adhesive compositions do not provide long-term stability especially after the sterilization. Cyanoacrylate adhesives combined with certain additives may cause significant histological response.
Cyanoacrylate adhesives are usually in the monomeric form when applied to a substrate. The subsequent polymerization of the cyanoacrylate affords the desired adhesive bond. However, the monomeric form of cyanoacrylate has a very low inherent viscosity which can result in the spreading of the adhesive into undesired areas. In order to obtain a cyanoacrylate adhesive composition with a desired higher viscosity, different thickening agents have been added to the adhesive compositions.
Organic or inorganic powders, which are not soluble in cyanoacrylate monomer, have been used as fillers to adjust the viscosity of cyanoacrylate compositions. Such materials include various inert inorganic materials such as silica, quartz, alumina, calcium and metal salts and organic powders such as polycarbonates, polyvinylidene fluorides, polyethylenes, and other polymeric powders. U.S. Pat. No. 4,533,422 discloses that cyanoacrylate compositions which employ fumed silicas as the filler are stable and exhibit a high thixotropic ratio. U.S. Pat. No. 3,607,542 discloses the preparation of a water-resistant cyanoacrylate paste containing insoluble, inert fillers such as salts of calcium, titanium, zinc, tin, aluminum, iron and copper, among others. U.S. Pat. No. 4,105,715 discloses the use of finely divided organic powders such as polycarbonates, polyvinylidene fluorides, polyethylenes, and other polymeric powders as additives for cyanoacrylates. Blending insolvable materials with cyanoacrylate compositions can cause separation while the adhesive is stored, resulting in ineffective modification of the viscosity. Also, the presence of the fillers can sometimes affect the quality of the adhesive bonding.
The most effective attempt so far to improve the viscosity of the cyanoacrylate adhesive compositions is combining various polymer additives to the cyanoacrylate monomer compositions. The polymer additives are soluble in cyanoacrylate compositions either at room or at elevated temperature.
For example, U.S. Pat. No. 3,282,773 to Wicker discloses cyanoacrylate adhesive compositions in which poly (methylmethacrylate) is used as the thickener.
U.S. Pat. No. 3,527,841 to Wicker et al. discloses a 2-cyanoacrylate adhesive composition for general use as well as for surgical use containing poly (lactic acid) as the viscosity thickener and an acidic compound such as sulfur dioxide and a free radical stabilizer such as hydroquinone.
U.S. Pat. No. 3,692,752 to Setsuda et al. discloses thickened cyanoacrylate solutions containing certain polyether acrylates/methacrylates, acrylic/methacrylic esters of bis(hydroxyalkyl)phosphonic acid derivatives, and acrylic/methacrylic esters of tris(hydroxyalkyl)cyanuric acid derivatives.
U.S. Pat. No. 4,102,945 to Gleave discloses a cyanoacrylate adhesive composition thickened by a copolymer or terpolymer resin capable of being dissolved or solvated by the cyanoacrylate monomer. Such cyanoacrylate adhesives exhibit significantly improved peel strength. Polymer thickeners disclosed by Gleave are acrylonitrile-butadiene-styrene terpolymers, methacrylate-butadiene-styrene terpolymers, and vinylidene chloride-acrylonitrile copolymers.
U.S. Pat. No. 5,328,687 to Leung et al. also discloses adhesive compositions that may be used for bonding tissue. The compositions contain polymers as thickening agents. Polymer thickeners employed include polylactic acid, polyglycolic acid, lactic-glycolic acid copolymers, polycaprolactone, lactic acid-caprolactone copolymers, poly-3-hydroxybutyric acid, polyorthoesters, polyalkyl acrylates, copolymers of alkylacrylate and vinyl acetate, polyalkyl methacrylates, and copolymers of alkyl methacrylates and butadiene.
U.S. Pat. No. 5,350,789 to Linden et al. discloses 2-cyanoacrylate-based tissue adhesives employing biocompatible oxalate polymers as reactive plasticizers and thickening agents. The adhesives are capable of being formulated to allow modulus matching of the adhesive and the substrate.
U.S. Pat. No. 5,665,817 to Greif et al. discloses alkyl cyanoacrylate compositions suitable for topical application to human skin, which comprise a suitable amount of a thickening agent to increase the viscosity. The thickening agent used is any biocompatible material that increases the viscosity of an alkyl cyanoacrylate composition including polymethylmethacrylate (PMMA) or other preformed polymers soluble in the alkyl cyanoacrylate. The thickening agent is added to provide a viscosity of from about 2 to 50,000 centipoises at 20° C.
U.S. Pat. No. 6,299,631 to Shalaby discloses bio-absorbable adhesive/hemostatic formulations of a 2-alkoxyalkylcyanoacrylate with trimethylene carbonate-based polymers as the viscosity thickener.
U.S. Pat. No. 4,038,345 to O'Sullivan et al. discloses stable cyanoacrylate adhesive compositions having improved viscosities. The adhesive compositions have viscosities in excess of about 500 centipoises comprising at least one monomeric ester of 2-cyanoacrylic acid, and a polyacrylate thickener which was pretreated to have a reduced viscosity greater than about 5. A free radical polymerization initiator in the amount of less than about one percent by weight is disclosed. The composition also contains an inhibitor for the anionic polymerization of the monomer. O'Sullivan discloses a process for preparing improved cyanoacrylates which involves heating a conventional polyacrylate thickener at a suitable temperature and for a suitable period of time to reduce its content of free radical polymerization initiators to below about one percent; and dissolving a sufficient amount of polymer thickener in the ester of 2-cyanoacrylic acid to produce a cyanoacrylate adhesive composition with suitable viscosity.
U.S. Pat. No. 6,797,107 to Kotzey et al. discloses a solid cyanoacrylate adhesive composition which can be applied to a substrate in solid form and which polymerizes into an adhesive polymer upon liquefying. The solid cyanoacrylate composition liquefies at temperatures slightly above room temperature and polymerizes upon liquification. ε-caprolactones are used as a solidifying polymer with cyanoacrylate monomers and other additives to form the solid cyanoacrylate adhesive composition.
U.S. Pat. No. 6,743,858 to Hickey et al. discloses a method of making a thickened sterile monomeric adhesive composition. Preparation of the composition includes placing a mixture of a polymerizable monomer and a thickening agent in a container, sealing the container and sterilizing the container and the mixture. The thickening agent is soluble in the monomer at room temperature. Suitable thickeners employed include, for example, polyoxalates, lactic-glycolic acid copolymers, polycaprolactone, lactic acid-caprolactone copolymers, poly (caporolactone+DL-lactide+glycolide), polyorthoesters, polyalkyl acrylates, copolymers of alkylacrylate and vinyl acetate, polyalkyl methacrylates, and copolymers of alkyl methacrylates and butadiene.
U.S. Pat. Appl. No. 20070092481 to Misiak et al. discloses a thickened cyanoacrylate adhesive composition by using poly[butyleneterephthalate-co-poly(ethyleneglycol) terephthalate] as the viscosity modifier. The formulation of cyanoacrylate adhesives in the form of low viscosity emulsions, non-flowable and gels forms could be prepared by adding this polymer component to the compositions.
Polymers of cyanoacrylates has also been used to modify the cyanoacrylate adhesive compositions. U.S. Pat. No. 2,794,788 teaches thickening of cyanoacrylate adhesives by dissolving polymeric alkyl cyanoacrylates, as well as other compounds including methacrylates, polyacrylates and cellulose esters. U.S. Pat. No. 3,527,224 to Rabinowitz discloses a surgical adhesive composition comprising monomeric and polymeric n-pentyl cyanoacrylate obtained by free-radical polymerization. U.S. Pat. Appl. No. 20060062687 to Morales discloses a method of sterilizing 2-cyanoacrylate compositions with poly-cyanoacrylate as the thickener, including heating the composition in a device at a temperature of from about 70° C. to about 140° C. for an effective amount of time. Morales discloses sterilization assays and 2-cyanoacrylate compositions for use in medicine or surgery. U.S. Pat. No. 3,564,078 discloses the use of poly (ethyl 2-cyanoacrylate) as a component of cyanoacrylate compositions.
The polymer additives previously used to improve the viscosity of the cyanoacrylate adhesive have not satisfactorily solved the conventional problem of this type of adhesive which is providing a stable, higher viscosity cyanoacrylate adhesive with properties desirable for medical applications. In some cases, only a relatively small modification of the viscosity is achieved by addition of polymers because the amount of the polymer thickener that can be added is limited due to the poor solubility of these polymers in the cyanoacrylate monomer. Adding too much polymer thickener to the adhesive compositions will result in spinnability, reduction of optical clarity and weakening of the adhesive bond. In addition, many polymer additives used as the thickening agents undergo decomposition under sterilization, which leads to the decreased viscosity. The instability of these cyanoacrylate adhesive compositions is exacerbated by the use of acid stabilizers. Acids destabilize the polymer thickener in these compositions. Presently, the only polymer thickeners which can be successfully used for commercial cyanoacrylate adhesive compositions include poly (methylmethacrylate) or poly(vinylacetate).
Another problem associated with cyanoacrylate adhesives is the relatively slow cure speed, especially those in compositions stabilized with a large amount of free radical and acid stabilizers. Cyanoacrylate adhesive compositions readily polymerize and cure in a short time without any catalysts or heating in the presence of anionic activators such as moisture or alkaline substances present on the solid substrates. However, the cure speed of the adhesives can be dramatically decreased if cyanoacrylate adhesives are applied to acidic substrates such as wood and paper. In addition, if a large amount of adhesive is applied in a relatively thick layer for example in a joint gap, rapid hardening throughout the adhesive may be difficult to achieve. In these cases, cyanoacrylate adhesives with a faster cure speed would provide a solution to these problems.
Various attempts have been made to shorten the cure time of cyanoacrylate adhesives. Different chemicals have been added to the cyanoacrylate adhesive compositions for this purpose. Accelerators used previously include detergent compositions; surfactants, amines, heterocyclic compounds, caffeine, aniline derivatives, urea, phosphines, alcohols, aromatic and aliphatic polyols, polyethylene glycols, inorganic bases and salts, sulfur compounds, polymeric cyclic ethers, crown ethers, calixarenes, cyclic and acyclic carbonates, and organometallics.
Japanese Patent Application No. JP-A-03 207 778 discloses the use of solutions of aliphatic, alicyclic and, especially, tertiary aromatic amines as the activators for the curing of cyanoacrylate adhesives. Specific examples included N,N-dimethylbenzylamine, N-methylmorpholine and N,N-diethyltoluidine. Japanese Patent Application No. JP-A-62 022 877 suggested the use of solutions of lower fatty amines, aromatic amines, and dimethylamine for the same purpose.
U.S. Pat. No. 4,042,442 to Dombroski et al. discloses the addition of a polymerization initiator such as caffeine or theobromine to a cyanoacrylate adhesive composition. The caffeine or theobromine may be added to the adhesive composition in different ways. The caffeine or theobromine can be dissolved in a volatile solvent, the volatile solvent is allowed to evaporate, and then the cyanoacrylate adhesive composition is applied to the surfaces of the substrates to be joined. Alternatively, the caffeine or theobromine can be mixed with the cyanoacrylate adhesive composition by stirring just prior to application of the adhesive to the substrates to be joined. Both of these methods are inconvenient for the user because two separate solutions or two separate applications are required.
British Patent No. 1 230 560 described cyanoacrylate adhesive compositions containing certain substituted heterocyclic compounds as accelerators. The compositions may be presented in a two-part form, the first part comprising the cyanoacrylate adhesive and the second part comprising at least one of the substituted heterocyclic compounds, preferably dissolved in an organic solvent. The heterocyclic compound is invariably present in one part of a two-part composition because iminoethylene-substituted triazines and pyrimido-yprimidines accelerate the polymerization so rapidly that they must be kept from the cyanoacryalte composition before use. An effective adhesive bond is obtained. This reference does not disclose an activator which is able to initiate polymerization throughout a layer of adhesive.
In U.S. Pat. No. 4,170,585 to Motegi et al., certain polyethylene glycols and poly(ethyleneoxy) are disclosed as additives for improving the curing speed of the cyanoacrylate compositions. In U.S. Pat. No. 4,377,490, aliphatic polyether and polyols have been used to modify 2-cyanoacrylate adhesive compositions.
U.S. Pat. No. 4,718,966 to Stephen. et al. discloses that cyanoacrylate adhesive compositions with calixarene compounds as accelerators give substantially reduced cure times on substrates such as wood, leather, ceramic, plastics and metals. The calixarene compounds are preferably employed at levels of about 0.1-1% by weight of the composition.
Japanese Patent Application No. 8-310136 to Ohashi, et al. discloses 2-cyanoacrylate adhesive compositions containing a crown ether or a polyalkylene oxide as the curing accelerator.
DE-A-40 09 621 proposed the use of certain cyclodextrin derivatives as additives to improve the cure speed of cyanoacrylate adhesives, some of which are soluble in cyanoacrylates. GB-A-2 200 124 revealed the use of acyclic phenol-formaldehyde oligomers as the accelerating additive for cyanoacrylate adhesive compositions.
Besides mixing the accelerators with the 2-cyanoacrylate adhesive, two component systems have also been proposed that package the cyanoacrylate adhesive and the accelerator separately. The disadvantage of this method is that accurate measurement of the accelerator and appropriate homogeneous mixing of the two components is difficult to achieve since only a trace amount of accelerator is generally required. U.S. Pat. No. 5,928,611 to Leung disclosed an applicator tip for dispensing a polymerizable material, in which a polymerization accelerator was included. The accelerator initiates polymerization when the cyanoacrylate adhesive liquid is dispensed through the applicator tip. Suitable accelerators include detergent compositions; surfactants, amines, urea, phosphines, alcohols, inorganic bases and salts, sulfur compounds, polymeric cyclic ethers, crown ethers, calixarenes, cyclic and acyclic carbonates, organometallics, and radical.
As illustrated above, a wide range of chemicals (small molecules or polymers) have been incorporated into the cyanoacrylate adhesive compositions either to improve the curing speed or to increase the viscosity of cyanoacrylate adhesives. However, most of the employed additives (thickeners or accelerators) exhibit various disadvantagest. Some of the accelerators or thickeners are toxic, while others exhibit weak effect, less bond strength, high volatility and odor. In addition, irregular structure is formed in some cases, which destroys transparency of the cyanoacrylate polymer film. Moreover, the stability and shelf life of cyanoacrylate adhesive compositions containing thickening agents or polymerization accelerators are always less than desirable. These shortcomings limit the application of the cyanoacrylate adhesives in different fields, especially for medical use. One goal of the present invention is, therefore, to use pluronic polymer additives to improve both the curing speed and the viscosity of the cyanoacrylate adhesives, particularly for use in medical applications.